Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis
- Authors
- Shi, D., Qi, M., Zhou, L., Li, X., Ni, L., Li, C., Yuan, T., Wang, Y., Chen, Y., Hu, C., Liang, D., Li, L., Liu, Y., Li, J., Chen, Y.H.
- ID
- ZDB-PUB-181026-10
- Date
- 2018
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology 38: 2665-2677 (Journal)
- Registered Authors
- Li, Jun, Li, Xiang
- Keywords
- endothelium, homeostasis, mitochondria, mitochondrial protein, zebrafish
- MeSH Terms
-
- Animals
- Brain/blood supply*
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Cells, Cultured
- Cerebrovascular Disorders/enzymology
- Cerebrovascular Disorders/genetics
- Endothelial Cells/enzymology*
- Endothelium, Vascular/embryology
- Endothelium, Vascular/enzymology*
- Gene Expression Regulation, Developmental
- Gene Expression Regulation, Enzymologic
- Humans
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice, Knockout
- Mitochondria/enzymology*
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism
- Neovascularization, Physiologic*/genetics
- Neuropeptides/genetics
- Neuropeptides/metabolism*
- Signal Transduction
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- rac1 GTP-Binding Protein/genetics
- rac1 GTP-Binding Protein/metabolism*
- PubMed
- 30354240 Full text @ Arterio., Thromb., and Vas. Bio.
Approach and Results- A combination of studies in the vascular-specific transgenic zebrafish and genetically engineered mice was conducted. Vascular casting and imaging, endothelial angiogenesis, and mitochondrial protein import were performed to dissect potential mechanisms. A loss-of-function genetic screening in zebrafish identified that selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities. Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function. Mechanistically, Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling, which incurred angiogenic impairment that underlies cerebrovascular network malformation.
Conclusions- Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium.